Coronary calcification is pathognomonic of coronary atherosclerosis, which is itself an essential pathophysiological step in the development of adverse coronary artery disease (CAD) outcomes. The coronary artery calcium score (CAC), as measured by non-contrast cardiac computed tomography (CT), is a measure of coronary atherosclerosis burden and has been consistently demonstrated to have added prognostic value in conjunction with traditional risk factor assessments. This incremental prognostic value has been shown both in persons at the extremes of traditional risk (based on traditional risk factors) and, most particularly, in those who are at intermediate risk by traditional assessment.²

The underlying reason for the prognostic value of CAC stems from the established association between increased CAC scores and atherosclerotic disease cardiovascular events (ASCVD), an association which is unrivaled in strength among ASCVD risk markers.^3-4 However, given the lack of randomized control trials (RCT) for the use of CAC, the role of cardiac CT to image CAC and guide clinical care has remained a much debated topic. In this piece, we will focus on reviewing the data on selective use of non-contrast cardiac CT to image CAC and inform the individualized management of ASCVD risk factors, with a focus on anti-hypertensive, statin, aspirin, and smoking cessation therapies.

Anti-hypertensives

Hypertension is a well-known cardiovascular risk factor and an important component of all ASCVD risk calculators in current clinical use. The traditional treatment paradigm has been to treat hypertension based on the absolute blood pressure (BP) irrespective of overall ASCVD risk. However, more recently, a growing body of evidence suggests that the clinical efficacy of BP therapy may vary with ASCVD risk.^5-7 Specifically, data show that for any given reduction in BP with therapy, the number of adults at high baseline ASCVD risk who need to be treated to prevent adverse outcomes is much less than the number needed for adults at low baseline risk.

For example, the Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated improved outcomes for major adverse cardiovascular events and death with target systolic BP (SBP) of 120 as compared with a target SBP of 140 for non-diabetic patients >50 years of age with increased cardiovascular risk, including patients above the age of 75.⁸ In contrast, the Heart Outcomes Prevention Evaluation Trial (HOPE-3) noted no benefit for BP treatment among patients with a mean baseline SBP of 138 who were intermediate risk for CAD,⁹ suggesting more lenient BP targets are reasonable in these patients. Only those patients with a systolic blood pressure in the upper tertile of subjects with a SBP of >140 had a reduction in their ASCVD risk.

Given the possibility that average benefit from anti-hypertensive treatment intensity can be estimated using ASCVD risk, CAC represents an additional metric that could be used to inform risk-based therapeutic decisions and therapeutic targets for BP management. The potential utility of CAC to better identify patients who are more likely to benefit from intensive BP therapy was reported in a recently published analysis of participants in the Multi-Ethnic Study of Atherosclerosis (MESA).¹⁰ In this modeling study, CAC appeared to be most suitable for guiding decisions around BP treatment intensity among adults with SBP 120-159 and a 10-year ASCVD risk score of 5 to 15%. Overall, participants with prehypertension (SBP 120-139) and mild hypertension (SBP 140-159) who had a CAC = 0 were noted to have low 10-year cardiovascular event rates.

Accordingly, the estimated number needed to treat (NNT) to prevent one ASCVD event for each patient treated to a more intensive SBP target was noted to be much higher (i.e., less net benefit) when CAC = 0 among patients with SBP 120-139 mmHg and in patients with SBP 140-159 mmHg, as compared with patients with a CAC between 1-100 and CAC > 100. All patients with a SBP > 160 and elevated ASCVD risk (≥15%) based on traditional equations had high event rates and lower estimated NNT regardless of CAC levels (and as such would likely benefit from a more intensive SBP target). Thus, this study suggests that the use of CAC may be able to inform more personalized BP goals (specifically, a target SBP of 120 rather than the traditional target of 140) for intermediate risk patients. For example, a CAC = 0 may allow for more liberal SBP goals and a focus on lifestyle measures, at least initially, while a CAC > 100 identifies those who may benefit from a more intense SBP target of 120 and, thus, who likely will require medical therapy early on.

Statins

Another potential use of CAC to guide ASCVD prevention is in statin initiation and allocation. The current cholesterol treatment guidelines from the American College of Cardiology (ACC) and the American Heart Association (AHA) underscore the importance of 10-year ASCVD risk estimation as an important metric to determine whether statin therapy will be beneficial for an individual patient.¹¹ They recommend that all adults with ASCVD risk ≥7.5% be treated after a risk-benefit discussion with the patient, and that those with risk of 5-7.4% also be considered for a statin. As a downstream consequence of these guidelines, about 13 million more adults are now eligible for statin therapy in the US.¹² Based on concerns that the current ASCVD equation may overestimate individual risk, there are significant questions about whether the 2013 guidelines will result in overuse of statin therapy.^13-14 In this setting, the case for more accurate risk stratification to identify lower risk patients and avoid unnecessary statin therapy is a strong one, especially considering the side effects and reportedly higher risk of diabetes with statin therapy.¹⁵

In patients who are recommended for consideration of statin therapy by guidelines, CAC is an option to better stratify risk and to guide more personalized therapeutic decision making. For example, in a study of MESA participants, Martin et al. noted that CAC stratifies cardiovascular risk regardless of the burden of dyslipidemia or how dyslipidemia is defined.¹⁶ In another MESA study evaluating persons who would have qualified for the Justification for the Use of Statins in Prevention: an Interventional Trial Evaluating Rosuvastatin (JUPITER) study, CAC provided improved risk stratification with a much higher NNT for CAC = 0 than for CAC 1-100 or CAC > 100.¹⁷ Nasir et al. also noted, in a similar study of MESA participants, that CAC = 0 is associated with a far lower cardiovascular event rate than that otherwise predicted by the traditional ASCVD risk score.18 Indeed, in those who were recommended for statin (i.e., those who had a calculated ASCVD risk estimate of ≥7.5%) and who also had CAC = 0, the actual observed 10-year ASCVD event rate was just 4.9%. In patients who should be considered for statin therapy (ASCVD risk 5-7.4%), those with CAC = 0 had a 10-year event rate of 1.5%. Both of these actual risk levels were below the recommended 7.5% treatment initiation threshold for strong consideration of statin therapy after a clinician-patient risk discussion.

The above study also suggests that CAC testing may have a limited impact on statin use in extremes of calculated 10-year ASCVD risk and, hence, may be better suited to informing care among intermediate risk adults. For example, in patients with a low calculated 10-year ASCVD risk of <5%, the observed 10-year event rates were below the threshold for statin treatment whether CAC = 0 or CAC > 0. Similarly, for participants with an ASCVD risk score of >20%, the observed 10-year event rates were consistently above the threshold to treat with statin therapy, whether or not CAC was zero.

The ACC/AHA risk assessment guidelines from 2013 recommend CAC imaging to enhance ASCVD risk estimation and prescription of statin therapy when uncertainty about therapy exists even after a clinician-patient risk benefit discussion, although this is only a class IIb recommendation.¹⁹ The cost effectiveness of CAC in the setting of statin therapy has been reported and CAC testing appears to be cost effective in intermediate risk patients compared to a treat all strategy.²⁰

Aspirin

While studied to a lesser extent, the potential use of CAC in consideration of aspirin (ASA) therapy has also been reported in a study of the MESA population by Miedema et al.²¹ This study reported that all participants with a CAC ≥ 100 had an estimated net benefit with ASA regardless of their risk status by traditional equations with an estimated 5-year NNT to prevent CVD of 173 in patients with a Framingham risk score (FRS) of <10%, an estimated 5-year NNT of 92 in patients with a FRS ≥ 10%, compared to an estimated 5-year number needed to harm (NNH) of 442 for major bleed. Conversely, individuals with CAC =0 were estimated to have more harm from ASA regardless of their risk status with a 5-year NNT to prevent CVD of 2036 for patients with a FRS < 10%, a 5-year NNT of 808 for patients with FRS ≥ 10% and a 5-year NNH of 442 for major bleed. Again, these results favor the selective use of CAC when the decision for ASA use is uncertain.

Smoking Cessation

The relationship between smoking and CAC scores has also been reported.^22-24 These data show that mortality and CVD outcomes for smokers with CAC > 0 are higher than for smokers with CAC = 0. In fact, at each stratum of elevated CAC score (1-99, 100-400 and >400), mortality in smokers is higher than mortality in non-smokers in the next highest CAC stratum. Patients with elevated CAC and active smoking warrant more dedicated time for discussion of smoking cessation. However, CAC = 0 in smokers cannot be used as a 'negative risk factor' since these patients have mortality rates similar to non-smokers with mild to moderate atherosclerosis. This is an important finding, given the interest in quantifying CAC among smokers who are eligible for low-dose chest CT screening for lung cancer.²²

Summary

There are a host of studies suggesting the benefit of CAC in guiding ASCVD prevention intensity. However, what is missing are randomized trials to confirm the compelling results from observational studies. This is important because the utility of CAC measurement is not without its potential drawbacks. Adding to cost and to patient anxiety, are incidental findings that are picked up on these CT scans and require further workup. Furthermore, the exposure to radiation is not insignificant, especially if follow up CT scans are performed, but a single CAC calcium scan is generally associated with the same amount of radiation as 1-2 mammogram (<1 millisievert). It should be emphasized here that the data presented above are observational and hypothesis generating. The case for a clinical trial involving CAC measurement has been made previously.²⁵ Randomized clinical trial data will be important to confirm the clinical efficacy of CAC and generate evidence robust enough to meaningfully affect routine clinical practice.

References

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Keywords: Antihypertensive Agents, Aspirin, Atherosclerosis, Blood Pressure, Cardiovascular Diseases, Cholesterol, Coronary Artery Disease, Diabetes Mellitus, Dyslipidemias, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypertension, Life Style, Risk Assessment, Risk Factors, Smoking, Smoking Cessation, Tomography, Tomography, X-Ray Computed

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